Quantification of cerebral blood flow as biomarker of drug effect: arterial spin labeling phMRI after a single dose of oral citalopram.

Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 6.85). 02/2011; 89(2):251-8. DOI: 10.1038/clpt.2010.296
Source: PubMed

ABSTRACT Arterial spin labeling (ASL) allows noninvasive quantification of cerebral blood flow (CBF), which can be used as a biomarker of drug effects in pharmacological magnetic resonance imaging (phMRI). In a double-blind, placebo-controlled crossover study, we investigated the effects of a single oral dose of citalopram (20 mg) on resting CBF in 12 healthy subjects, using ASL phMRI. Support-vector machine (SVM) analysis detected significant drug-induced reduction in CBF in brain regions including the amygdala, fusiform gyrus, insula, and orbitofrontal cortex. These regions have been shown to have abnormally elevated CBF in patients with major depression, as well as in subjects genetically prone to depression. Mixed-effects analysis on data extracted from selected regions of interest (ROIs) revealed significant drug effect only in serotonergic areas of the brain (z = -4.45, P < 0.005). These results demonstrate the utility of ASL phMRI as a biomarker of pharmacological activity of orally administered drugs in the brain.

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    ABSTRACT: Background Animal and human studies highlight the role of oxytocin in social cognition and behaviour and the potential of intranasal oxytocin (IN-OT) to treat social impairment in neuropsychiatric disorders such as autism. However, extensive efforts to evaluate its central actions and therapeutic efficacy may be marred by the absence of data regarding its temporal dynamics and sites of action in the living human brain. Methods In a placebo-controlled study, we used arterial spin labeling to measure IN-OT induced changes in resting regional cerebral blood flow (rCBF) in 32 healthy men. Volunteers were blinded regarding the nature of the compound they received. rCBF data were acquired 15min before and up to 78min following treatment onset (40IU of IN-OT or placebo). The data were analysed using mass-univariate and multivariate PR techniques. Results We obtained robust evidence delineating an oxytocinergic network comprising regions expected to express oxytocin receptors, based on histological evidence, and including core regions of the brain circuitry underpinning social cognition and emotion processing. PR on rCBF maps indicated that IN-OT induced changes were sustained over the entire post-treatment observation interval (25-78min) and consistent with a pharmacodynamic profile showing a peak response at 39-51min. Conclusions Our study provides the first visualisation and quantification of IN-OT induced changes in rCBF in the living human brain unaffected by cognitive, affective, or social manipulations. Our findings can inform theoretical and mechanistic models regarding IN-OT effects on typical and atypical social behaviour and guide future experiments (e.g. regarding the timing of experimental manipulations).
    Biological Psychiatry 10/2014; · 9.47 Impact Factor
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    ABSTRACT: A carefully controlled study allowed us to compare the sensitivity of ASL (arterial spin labeling) and BOLD (blood oxygen level dependent) fMRI for detecting the effects of the adenosine A2a antagonist tozadenant in Parkinson disease. The study compared the effect of drug directly or the interaction of the drug with a cognitive task. Only ASL detected the direct effect of tozadenant. BOLD was more sensitive to the cognitive task, which (unlike most drugs) allows on-off comparisons over short periods of time. Neither ASL nor BOLD could detect a cognitive-pharmacological interaction. These results are consistent with the known relative advantages of each fMRI method, and suggest that for drug development, directly imaging pharmacodynamic effects with ASL may have advantages over cognitive-pharmacological interaction BOLD, which has hitherto been the more common approach to pharmacological fMRI.
    PeerJ. 12/2014; 2:e687.
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    ABSTRACT: Resting-state functional connectivity (FC) fMRI (rs-fcMRI) offers an appealing approach to mapping the brain's intrinsic functional organization. Blood oxygen level dependent (BOLD) and arterial spin labeling (ASL) are the two main rs-fcMRI approaches to assess alterations in brain networks associated with individual differences, behavior and psychopathology. While the BOLD signal is stronger with a higher temporal resolution, ASL provides quantitative, direct measures of the physiology and metabolism of specific networks. This study systematically investigated the similarity and reliability of resting brain networks (RBNs) in BOLD and ASL. A 2×2×2 factorial design was employed where each subject underwent repeated BOLD and ASL rs-fcMRI scans on two occasions on two MRI scanners respectively. Both independent and joint FC analyses revealed common RBNs in ASL and BOLD rs-fcMRI with a moderate to high level of spatial overlap, verified by Dice Similarity Coefficients. Test-retest analyses indicated more reliable spatial network patterns in BOLD (average modal Intraclass Correlation Coefficients: 0.905±0.033 between-sessions; 0.885±0.052 between-scanners) than ASL (0.545±0.048; 0.575±0.059). Nevertheless, ASL provided highly reproducible (0.955±0.021; 0.970±0.011) network-specific CBF measurements. Moreover, we observed positive correlations between regional CBF and FC in core areas of all RBNs indicating a relationship between network connectivity and its baseline metabolism. Taken together, the combination of ASL and BOLD rs-fcMRI provides a powerful tool for characterizing the spatiotemporal and quantitative properties of RBNs. These findings pave the way for future BOLD and ASL rs-fcMRI studies in clinical populations that are carried out across time and scanners. Copyright © 2014 Elsevier Inc. All rights reserved.
    NeuroImage 11/2014; 106. · 6.13 Impact Factor